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WO2022198905A1 - Dérivé tricyclique, son procédé de préparation et son utilisation - Google Patents

Dérivé tricyclique, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2022198905A1
WO2022198905A1 PCT/CN2021/113481 CN2021113481W WO2022198905A1 WO 2022198905 A1 WO2022198905 A1 WO 2022198905A1 CN 2021113481 W CN2021113481 W CN 2021113481W WO 2022198905 A1 WO2022198905 A1 WO 2022198905A1
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Prior art keywords
group
alkyl
halogen
cancer
heteroaryl
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/CN2021/113481
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English (en)
Chinese (zh)
Inventor
陈友喜
龚亮
向清
毛文涛
赵雯雯
赵伟峰
叶成
钱文建
陈磊
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Zhejiang Hisun Pharmaceutical Co Ltd
Hisun Accuray Therapeutics Co Ltd
Original Assignee
Zhejiang Hisun Pharmaceutical Co Ltd
Hisun Accuray Therapeutics Co Ltd
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Publication of WO2022198905A1 publication Critical patent/WO2022198905A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a tricyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a KRas G12D inhibitor.
  • RAS represents a group of closely related monomeric globular proteins (21 kDa molecular weight) that have 189 amino acids and are associated with the plasma membrane and bind GDP or GTP. Under normal developmental or physiological conditions, RAS is activated upon receipt of growth factors and various other extracellular signals, and is responsible for regulating functions such as cell growth, survival, migration, and differentiation. RAS acts as a molecular switch, and the on/off state of RAS proteins is determined by nucleotide binding, with the active signaling conformation bound to GTP and the inactive conformation bound to GDP. When RAS contains bound GDP, it is in a dormant or quiescent or off state and is "inactive".
  • RAS When cells respond to exposure to certain growth-promoting stimuli, RAS is induced to convert bound GDP to GTP. With GTP bound, RAS is "on” and is able to interact with and activate other proteins (its “downstream targets”).
  • the RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP and thereby turn itself into the off state. Switching RAS off requires exogenous proteins called GTPases activating proteins (GAPs), which interact with RAS and greatly facilitate the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or convert GTP back to GDP will result in prolonged activation of the protein and thus an extended signal to the cell that tells it to continue growing and split. So these signals allow cells to grow and divide, and overactive RAS signaling may ultimately lead to cancer.
  • RAS proteins contain a G domain responsible for the enzymatic activity of RAS, guanine nucleotide binding and hydrolysis (GTPase reaction). It also includes a C-terminal extension called the CAAX box, which can be post-translationally modified and target the protein to the membrane.
  • the G domain is approximately 21-25 kDa in size and contains a phosphate-binding loop (P-loop).
  • P-loop represents the pocket in the protein that binds nucleotides, and this is the rigid part of the domain with conserved amino acid residues necessary for nucleotide binding and hydrolysis (glycine 12, threo amino acid 26 and lysine 16).
  • the G domain also contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), both of which are the dynamic part of the protein as it switches between rest and load states capability is often denoted as a "spring loaded” mechanism.
  • the main interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the ⁇ -phosphate of GTP, which allows switch I and switch II regions, respectively, to maintain their active conformations. After hydrolysis of GTP and release of phosphate, both relax to the inactive GDP conformation.
  • KRAS mutations are prevalent in the three most lethal cancer types in the United States: pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (25%). KRAS mutations are also found in other cancer types including carcinoma, diffuse large B-cell lymphoma, rhabdomyosarcoma, cutaneous squamous cell carcinoma, cervical cancer, testicular germ cell carcinoma, etc. Rarely found ( ⁇ 2%).
  • NSCLC non-small cell lung cancer
  • KRAS G12C is the most common mutation, accounting for nearly half of all KRAS mutations, followed by G12V and G12D.
  • KRAS mutations in lung cancer including G12C
  • KRAS mutations frequently co-occur with certain co-mutations, such as STK11, KEAP1, and TP53, which cooperate with mutated RAS to transform cells into highly malignant and aggressive tumor cells.
  • KRas G12D inhibitors At present, there is fierce competition for clinical development of KRas G12D inhibitors at home and abroad. Among them, MRTX-1133, a KRas G12D inhibitor developed by Mirati Therapeutics Inc, has entered the preclinical stage for the treatment of colorectal tumors, non-small cell lung cancer and pancreatic cancer. . At present, there are a few patent applications for KRas G12D inhibitors published, including WO2021041671 of Mirati Therapeutics Inc. Although some progress has been made in the research and application of KRas G12D inhibitors, the room for improvement is still huge, and it is still necessary to continue the research and development of new KRas G12D inhibitors.
  • the object of the present invention is to provide a tricyclic derivative represented by the general formula (I), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:
  • G is selected from a 4-12 membered heterocyclic group containing 1-2 nitrogen atoms, wherein the heterocyclic group is optionally further substituted by one or more R c ;
  • X and Y are each independently selected from N or CR f ;
  • Ring A is selected from 5-6 membered heteroaryl
  • R f is selected from hydrogen atom, halogen, alkyl or alkoxy; wherein said alkyl or alkoxy is optionally further selected by one or more groups selected from halogen, hydroxyl, cyano, alkyl or alkoxy Substituents are substituted; R f is preferably halogen, more preferably fluorine or chlorine;
  • R 1 is selected from hydrogen atom, halogen, alkyl or alkoxy; wherein said alkyl or alkoxy is optionally further selected from one or more groups selected from halogen, hydroxyl, cyano, alkyl or alkoxy Substituents are substituted; R 1 is preferably a hydrogen atom;
  • R is selected from absence, hydrogen atom, halogen, alkyl, alkoxy, cyano, haloalkyl or haloalkoxy, preferably absence or hydrogen atom;
  • R 7 , R 8 and R 9 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group , aryl or heteroaryl are optionally further selected from one or more groups selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , substituted by a substituent of a carboxyl group or a carboxylate group;
  • n is selected from 0, 1 or 2;
  • r 0, 1 or 2.
  • -G-H are selected from:
  • R c are the same or different, each independently selected from hydrogen atom, halogen, alkyl or alkoxy, preferably alkyl, more preferably methyl;
  • n is selected from 0, 1, 2, 3 or 4.
  • R 2 is selected from phenyl, naphthyl, pyridyl, benzothiazolyl or benzopyrazolyl, wherein said phenyl, naphthyl, pyridyl, benzothiazolyl or benzopyrazolyl is optionally further is substituted by one or more substituents selected from halogen, hydroxy, alkyl, alkoxy, cycloalkyl or -NR5R6 , wherein said alkyl or alkoxy is optionally further substituted by one or more A substituent selected from halogen or -NR 5 R 6 is substituted; wherein the halogen is preferably fluorine;
  • R 5 and R 6 are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is preferably a methyl group.
  • Typical compounds of the present invention include, but are not limited to:
  • the present invention provides the preparation method of the compound of general formula (I) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, the method is:
  • the compound of general formula (IA) and the compound of general formula (IB) are subjected to Suzuki coupling reaction under the action of a palladium catalyst and a basic reagent, and the protecting group is further removed to obtain the compound of general formula (I);
  • X 1 is a leaving group, preferably chlorine
  • M is selected from -B(OH) 2 , -BF 3 K or
  • PG is a protecting group, preferably tert-butoxycarbonyl
  • the present invention provides a compound of the general formula (IA) or a stereoisomer, a tautomer and a pharmaceutically acceptable salt thereof,
  • X 1 is a leaving group, preferably chlorine
  • PG is a protecting group, preferably tert-butoxycarbonyl
  • Rings A, R 1 , R 3 , X, Y, G and n are as defined in general formula (I).
  • Typical compounds of formula (IA) include, but are not limited to:
  • the present invention provides a pharmaceutical composition containing an effective dose of the compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable thereof and pharmaceutically acceptable carriers, excipients or their combinations.
  • the present invention provides a method for inhibiting KRas G12D enzyme, wherein the method comprises administering to a patient a pharmaceutical composition containing an effective dose of the compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.
  • the present invention also provides a compound of the general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the treatment is mediated by the KRas G12D mutation.
  • said disease mediated by KRas G12D mutation is selected from cancer, wherein said cancer is selected from cardiac myxoma, lung cancer, gastric cancer, colorectal tumor, rectal cancer, pancreatic cancer, prostate cancer , bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenal neuroblastoma, bone marrow leukemia, acute lymphoblastic leukemia or glioblastoma; wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
  • the present invention provides a compound of the general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a KRas G12D inhibitor use in.
  • Another aspect of the present invention relates to a method for preventing and/or treating a disease mediated by KRas G12D mutation, comprising administering to a patient a therapeutically effective dose of a compound represented by general formula (I) or a tautomer thereof, Meso, racemate, enantiomer, diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
  • the present invention also provides a compound of the general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition thereof in the preparation of a medicament for treating cancer , wherein the cancer is selected from cardiac myxoma, lung cancer, gastric cancer, colorectal tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine carcinoma, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphoblastic leukemia or glioblastoma; wherein the lung cancer is selected from non-small cell carcinoma cell lung cancer or small cell lung cancer.
  • compositions of the present invention can be topical, oral, transdermal, rectal, vaginal, parenteral, intranasal, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intradermal , intraperitoneal, subcutaneous, substratum corneum, or by inhalation.
  • Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • the formulations of the present invention are suitably presented in unit dosage form, and such formulations may be prepared by any method well known in the art of pharmacy.
  • the amount of active ingredient that can be combined with carrier materials to produce a single dosage form can vary depending upon the host treated and the particular mode of administration.
  • the amount of active ingredient which, in combination with a carrier material, can produce a single dosage form generally refers to that amount of compound which produces a therapeutic effect.
  • Dosage forms for topical or transdermal administration of the compounds of this invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and it can be mixed with any preservatives, buffers or propellants that may be required.
  • the compounds of the present invention When the compounds of the present invention are administered in pharmaceutical form to humans and animals, the compounds may be provided alone or in a pharmaceutical composition containing in combination with a pharmaceutically acceptable carrier active ingredient, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient.
  • a pharmaceutically acceptable carrier active ingredient for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient.
  • Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and derivatives thereof such as carboxylate (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and Suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol , mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) seaweed (16) pyrogen-free water; (17) isotonic saline; (18) Ring
  • antioxidants examples include, but are not limited to: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; ( 2) Oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like
  • Oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (B
  • Solid dosage forms may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or the following Any one of: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as carboxymethyl cellulose, alginate, Gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) humectants, such as cetyl alcohol and glycerol monostearate; (8)
  • Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzene Methanol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuran methanol, polyethylene Diols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as water or other solvents
  • solubilizers and emulsifiers such as ethanol
  • Suspensions in addition to the active compounds, may also contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar-agar and tragacanth and mixtures thereof.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar-agar and tragacanth and mixtures thereof.
  • Ointments, pastes, creams and gels can contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, poly Ethylene glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, poly Ethylene glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.
  • Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • the sprays can contain other customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Alkyl when taken as a group or part of a group is meant to include C1 - C20 straight or branched chain aliphatic hydrocarbon groups. Preferably it is a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.
  • Alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups can be optionally substituted or unsubstituted.
  • Alkynyl refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preferred are C2 - C10 alkynyl groups, more preferably C2 - C6 alkynyl groups, and most preferably C2 - C4 alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.
  • Cycloalkyl refers to saturated or partially saturated monocyclic, fused, bridged and spirocyclic carbocyclic rings. Preferably it is C 3 -C 12 cycloalkyl, more preferably C 3 -C 8 cycloalkyl, most preferably C 3 -C 6 cycloalkyl.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl groups can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called spiro atom) with each other, and the ring contains one or more aromatic systems with double bonds but none of the rings have fully conjugated pi electrons.
  • spiro atom carbon atom
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocycloalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • fused cycloalkyl include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthryl.
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged cycloalkyl include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-dicyclo[3.2.1]octyl Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.
  • Heterocyclyl “heterocycle,” or “heterocyclic” are used interchangeably herein to refer to a non-aromatic heterocyclyl in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged and spiro rings. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, piperidinyl , 2-oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl .
  • Heterocyclyl groups can be substituted or unsubstituted.
  • “Spiroheterocyclyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and single rings share one atom with each other, and the ring contains one or more double bonds, but no An aromatic system with fully conjugated pi electrons in one ring, wherein one or more ring atoms are selected from nitrogen, oxygen, or a heteroatom of S(O) r (wherein r is selected from 0, 1, or 2), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • Spirocycloalkyl groups are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl according to the number of spiro atoms shared between rings, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • spiroheterocyclyl include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl Heterospiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.
  • “Fused heterocyclic group” refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms with each other, one or more rings may contain one or more double bonds, but no ring has complete Conjugated pi-electron aromatic systems wherein one or more ring atoms are selected from nitrogen, oxygen or heteroatoms of S(O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0] Hexyl, octahydrobenzo[b][1,4]dioxine.
  • “Bridged heterocyclyl” refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more cyclic structures that share two atoms that are not directly connected to each other, and one or more rings may be Aromatic systems containing one or more double bonds but none of the rings have fully conjugated pi electrons, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2), the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo Cyclo[3.3.2]decyl.
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C6 - C10 aryl groups, more preferred aryl groups are phenyl and naphthyl.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5 to 6 membered monocyclic or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include but are not limited to furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiazolyl oxadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl,
  • Heteroaryl groups can be substituted or unsubstituted.
  • Alkoxy refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Ci - C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl means a group in which an alkyl group is optionally further substituted with one or more halogens, wherein alkyl is as defined herein.
  • Hydroalkyl refers to a group in which an alkyl group is optionally further substituted with one or more hydroxy groups, wherein alkyl is as defined herein.
  • Haloalkoxy refers to a group in which the alkyl group of (alkyl-O-) is optionally further substituted with one or more halogens, wherein alkoxy is as defined herein.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl refers to -CH2 -phenyl.
  • Carboxyl refers to -C(O)OH.
  • Carboxylate means -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.
  • DMSO dimethyl sulfoxide
  • BOC refers to t-butoxycarbonyl
  • Ts refers to p-toluenesulfonyl.
  • T3P refers to propylphosphoric anhydride.
  • DPPA diphenylphosphoryl azide
  • DEA diethylamine
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • R 6 and R 7 together with the atoms to which they are attached form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(O) r , and the
  • R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group , aryl or heteroaryl are optionally further selected from one or more groups selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , substituted by a substituent of a carboxyl group or a carboxylate group;
  • r 0, 1 or 2.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are contemplated, including but not limited to diastereomers, enantiomers, and atropisomers and geometric (conformational) isomers and Their mixtures, such as racemic mixtures, are within the scope of the present invention.
  • the structures depicted herein also include all isomeric (eg, diastereomeric, enantiomeric, and atropisomeric and geometric (conformational) isomeric forms of such structures; for example, , the R and S configuration of each asymmetric center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers.
  • isomeric eg, diastereomeric, enantiomeric, and atropisomeric and geometric (conformational) isomeric forms of such structures; for example, , the R and S configuration of each asymmetric center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers.
  • the individual stereoisomers of the compounds of the present invention as well as Enantiomeric mixtures, diastereomeric mixtures and geometric (conformational) isomer mixtures are all within the scope of the present invention.
  • “Pharmaceutically acceptable salts” refers to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) may be a metal salt or an amine salt with a suitable acid.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients Form.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (IA) and the compound of general formula (IB) are subjected to Suzuki coupling reaction under the action of a palladium catalyst and a basic reagent, and the protecting group is further removed to obtain the compound of general formula (I);
  • X 1 is a leaving group, preferably chlorine
  • M is selected from -B(OH) 2 , -BF 3 K or
  • PG is a protecting group, preferably tert-butoxycarbonyl
  • Rings A, R 1 to R 3 , X, Y, G and n are defined as in the general formula (I).
  • Mass spectrum is obtained by LC/MS instrument, and the ionization mode can be ESI or APCI.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • CD3OD Deuterated methanol.
  • the compound was purified using column chromatography and thin layer chromatography eluent system, wherein the system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system, D: dichloromethane and ethanol system, E: ethyl acetate and tetrahydrofuran system, wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added to carry out the condition , such as acetic acid or triethylamine, etc.
  • Test Example 1 Determination of the Inhibitory Activity of the Compounds of the Invention on p-ERK1/2 in AGS Cells
  • the following method was used to determine the inhibitory activity of the compounds of the present invention on p-ERK1/2 in AGS cells.
  • This method uses the Advanced phospho-ERK1/2 (Thr202/tyr204) kit (Cat. No. 64AERPEH) from Cisbio.
  • kit instructions for detailed experimental operations, please refer to the kit instructions.
  • AGS cells (containing KRAS G12D mutation) were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
  • AGS cells were cultured in F12K complete medium containing 10% fetal bovine serum, 100 U penicillin and 100 ⁇ g/mL streptomycin.
  • AGS cells were plated in 96-well plates at 40,000 cells per well, and the medium was complete medium, and cultured overnight in a 37° C., 5% CO2 incubator.
  • the test compound was dissolved in DMSO to prepare a 10mM stock solution, then diluted with F12K complete medium, and 100uL of F12K complete medium containing the corresponding concentration of the test compound was added to each well.
  • the final concentration range of the test compound in the reaction system After culturing in a cell incubator for 3 hours, discard the cell supernatant, wash the cells with ice-bathed PBS, and then add 50 ⁇ l of 1 ⁇ cell phospho/total protein lysis buffer (Advanced phospho-ERK1 /2 kit components) were lysed, the 96-well plate was placed on ice for half an hour, and then the lysate was detected according to the instructions of the Advanced phospho-ERK1/2 (Thr202/tyr204) kit.
  • 1 ⁇ cell phospho/total protein lysis buffer Advanced phospho-ERK1 /2 kit components
  • the fluorescence intensity of each well at 620nM and 665nM was measured on a microplate reader in TF-FRET mode, and the fluorescence intensity ratio of 665/620 in each well was calculated.
  • the percentage inhibition rate of the test compound at each concentration was calculated, and the numerical-inhibition rate was subjected to nonlinear regression analysis with the test compound concentration by GraphPad Prism 5 software. , to obtain the IC50 value of the compound.
  • the preferred compound of the present invention has obvious inhibitory effect on the activity of p-ERK1/2 in AGS cells, the preferred compound has an IC 50 ⁇ 500nM, and the more preferred compound has an IC 50 ⁇ 200nM.
  • Test Example 2 The compound of the present invention inhibits the proliferation of AsPC-1 cells
  • AsPC-1 cells (containing KRAS G12D mutation) were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U penicillin, 100 ⁇ g/mL streptomycin and 1 mM Sodium Pyruvate middle. cell viability through Assays were performed with the Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).
  • test compound was first dissolved in DMSO to prepare a 10 mM stock solution, and then diluted with culture medium to prepare a test sample.
  • the final concentration of the compound was in the range of 1000nM-0.015nM .
  • Cells in logarithmic growth phase were seeded into 96-well cell culture plates at a density of 800 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, followed by the addition of test compounds for 120 hours. After the incubation, 50uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, and then allowed to stand for 10 minutes.
  • the luminescence value of each well of the sample was read on a microplate reader using Luminescence mode.
  • the percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.3% DMSO), and then a nonlinear regression analysis was performed in the GraphPad Prism 5 software with the compound concentration logarithm-inhibition rate to obtain the compound inhibiting cell proliferation. the IC50 value.
  • the preferred compound of the present invention has obvious inhibitory effect on the proliferation of AsPC-1 cells, the preferred compound has an IC 50 ⁇ 500nM, and the more preferred compound has an IC 50 ⁇ 200nM.

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Abstract

La présente invention concerne un dérivé tricyclique, son procédé de préparation et son application en médecine. Plus particulièrement, la présente invention concerne un dérivé tricyclique représenté par la formule générale (I), son procédé de préparation et un sel pharmaceutique de celui-ci, et l'utilisation du dérivé tricyclique et du sel pharmaceutique en tant qu'agent thérapeutique, en particulier en tant qu'inhibiteur de KRas G12D, les définitions des substituants dans la formule générale (I) étant les mêmes que celles dans la description.
PCT/CN2021/113481 2021-03-26 2021-08-19 Dérivé tricyclique, son procédé de préparation et son utilisation Ceased WO2022198905A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025080592A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie à base d'un inhibiteur de kras g12d et d'un inhibiteur d'egfr pour une utilisation dans le traitement du cancer
WO2025080593A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie utilisant un inhibiteur de kras g12d et un inhibiteur de pd-1 ou un inhibiteur de pd-l1
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054846A1 (fr) * 2009-11-05 2011-05-12 Glaxosmithkline Llc Derives d'imidazo [4, 5-c] quinoline comme inhibiteurs de bromodomaine
WO2016199943A1 (fr) * 2015-06-11 2016-12-15 Takeda Pharmaceutical Company Limited Composés hétérocycliques
CN107835812A (zh) * 2015-04-03 2018-03-23 南特生物科学股份有限公司 靶向突变体k‑ras 的组合物和方法
CN108779097A (zh) * 2015-11-16 2018-11-09 亚瑞克西斯制药公司 包含取代的杂环基的2-取代的喹唑啉化合物及其使用方法
CN109843856A (zh) * 2016-05-18 2019-06-04 米拉蒂治疗股份有限公司 Kras g12c抑制剂
CN110267957A (zh) * 2017-02-02 2019-09-20 安斯泰来制药株式会社 喹唑啉化合物
WO2020037091A1 (fr) * 2018-08-16 2020-02-20 Innate Tumor Immunity, Inc. Modulateurs de nlrp3 dérivés d'imidazo [4,5-c]quinoléine
CN111377918A (zh) * 2019-11-29 2020-07-07 苏州信诺维医药科技有限公司 一种kras抑制剂化合物
CN111989321A (zh) * 2017-11-15 2020-11-24 米拉蒂治疗股份有限公司 Kras g12c抑制剂
WO2020238791A1 (fr) * 2019-05-24 2020-12-03 江苏恒瑞医药股份有限公司 Dérivé d'hydropyridopyrimidine, son procédé de préparation et son utilisation médicale
CN112047948A (zh) * 2019-06-06 2020-12-08 山东轩竹医药科技有限公司 Kras突变体抑制剂
WO2020245430A1 (fr) * 2019-06-07 2020-12-10 Instituto De Medicina Molecular Joao Lobo Antunes Benzo[h][1,6] naphtyridin-2(1h)-ones utilisés en tant qu'inhibiteurs de bmx destinés à être utilisés contre le cancer
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2021142252A1 (fr) * 2020-01-10 2021-07-15 Incyte Corporation Composés tricycliques en tant qu'inhibiteurs de kras

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054846A1 (fr) * 2009-11-05 2011-05-12 Glaxosmithkline Llc Derives d'imidazo [4, 5-c] quinoline comme inhibiteurs de bromodomaine
CN107835812A (zh) * 2015-04-03 2018-03-23 南特生物科学股份有限公司 靶向突变体k‑ras 的组合物和方法
WO2016199943A1 (fr) * 2015-06-11 2016-12-15 Takeda Pharmaceutical Company Limited Composés hétérocycliques
CN108779097A (zh) * 2015-11-16 2018-11-09 亚瑞克西斯制药公司 包含取代的杂环基的2-取代的喹唑啉化合物及其使用方法
CN109843856A (zh) * 2016-05-18 2019-06-04 米拉蒂治疗股份有限公司 Kras g12c抑制剂
CN110267957A (zh) * 2017-02-02 2019-09-20 安斯泰来制药株式会社 喹唑啉化合物
CN111989321A (zh) * 2017-11-15 2020-11-24 米拉蒂治疗股份有限公司 Kras g12c抑制剂
WO2020037091A1 (fr) * 2018-08-16 2020-02-20 Innate Tumor Immunity, Inc. Modulateurs de nlrp3 dérivés d'imidazo [4,5-c]quinoléine
WO2020238791A1 (fr) * 2019-05-24 2020-12-03 江苏恒瑞医药股份有限公司 Dérivé d'hydropyridopyrimidine, son procédé de préparation et son utilisation médicale
CN112047948A (zh) * 2019-06-06 2020-12-08 山东轩竹医药科技有限公司 Kras突变体抑制剂
WO2020245430A1 (fr) * 2019-06-07 2020-12-10 Instituto De Medicina Molecular Joao Lobo Antunes Benzo[h][1,6] naphtyridin-2(1h)-ones utilisés en tant qu'inhibiteurs de bmx destinés à être utilisés contre le cancer
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
CN111377918A (zh) * 2019-11-29 2020-07-07 苏州信诺维医药科技有限公司 一种kras抑制剂化合物
WO2021142252A1 (fr) * 2020-01-10 2021-07-15 Incyte Corporation Composés tricycliques en tant qu'inhibiteurs de kras

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025080592A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie à base d'un inhibiteur de kras g12d et d'un inhibiteur d'egfr pour une utilisation dans le traitement du cancer
WO2025080593A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie utilisant un inhibiteur de kras g12d et un inhibiteur de pd-1 ou un inhibiteur de pd-l1

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